CN1447797A - New process for preparing quinolone-carboxylic acid - Google Patents

New process for preparing quinolone-carboxylic acid Download PDF

Info

Publication number
CN1447797A
CN1447797A CN01814188.9A CN01814188A CN1447797A CN 1447797 A CN1447797 A CN 1447797A CN 01814188 A CN01814188 A CN 01814188A CN 1447797 A CN1447797 A CN 1447797A
Authority
CN
China
Prior art keywords
chloro
compound
formula
fluoro
bis
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN01814188.9A
Other languages
Chinese (zh)
Other versions
CN1219769C (en
Inventor
王允才
陈荣业
南海军
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Dalian Luyuan New Chemical Co ltd
Original Assignee
Dalian Luyuan New Chemical Co ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Dalian Luyuan New Chemical Co ltd filed Critical Dalian Luyuan New Chemical Co ltd
Publication of CN1447797A publication Critical patent/CN1447797A/en
Application granted granted Critical
Publication of CN1219769C publication Critical patent/CN1219769C/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/80—Ketones containing a keto group bound to a six-membered aromatic ring containing halogen
    • C07C49/807—Ketones containing a keto group bound to a six-membered aromatic ring containing halogen all halogen atoms bound to the ring

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Quinoline Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

The invention provides a process for preparing a quinolone-carboxylic acid derivatives of formula (I), wherein: R1 is H, halogen, NH2; R2 is halogen; R3 is H, halogen, C1-C4 alkoxy, CN; R4 is C3-C6 cycloalkyl, C1-C4 alkyl, C1-C4 alkoxy C1-C4 alkyl, C1-C4 alkylamino C1-C4 alkyl. The invention also provides a new intermediate of acetophenone of formula (II).

Description

The preparation method of new quinolonecarboxylic acid
01 01156
The preparation method field of the present invention of new quinolonecarboxylic acid
The present invention relates to the preparation method of quinolonecarboxylic acid, the method that quinolonecarboxylic acid is more particularly to prepared by raw material of phenyl polyhalide ethyl ketone.Technical background
Quinolones anti-infectives, due to its excellent performance, obtain people and widely pay close attention in recent years.Quinolonecarboxylic acid is the important intermediate of this kind of anti-infectives, and various QNSs are, using these intermediates as precursor, then to walk synthesis by number and derive invariably.Therefore, these quinolonecarboxylic acids are synthesized obviously extremely important during QNS is prepared.The method of a variety of synthesis quinolonecarboxylic acids had been reported already, such as from 2,4, the fluoro- 3- methoxy benzoic acids of 5- tri- synthesis Moses's carboxylic acid, the synthesis department carboxylic acid fluoride since pentafluoro benzoic acid, but these methods on yield and not up to highly satisfactory effect, therefore, still there is the space of improvement.The present invention is proposed based on this.Present invention general introduction
An object of the present invention is to provide a kind of novel method for preparing quinolonecarboxylic acid, starts with synthesis quinolonecarboxylic acid from raw material phenyl polyhalide ethyl ketone.The method and step of the present invention is relatively fewer, can reach ideal yield.The method of the preparation formula (I) quinolonecarboxylic acid of the present invention,
(0
Figure IMGF000002_0001
Wherein：^ is halogen atom, amino,
R2For halogen atom,
R3For Hydrogen, halogen atom,（^-^ protective embankment epoxides, CN,
14For3- (36Ring protective embankment base, protective embankment base,（ C4Protective embankment epoxide C C4Protective embankment base, c c4 c c4
Including step：
I) by formula (II) compound
Figure IMGF000003_0001
Wherein R R2, R3It is defined as above, R7For halogen atom,
Formula (Ι Π) compound is obtained with carbonate reaction,
Figure IMGF000003_0002
Wherein, R8Represent methyl or ethyl；
Ii formula (V) compound) is obtained with formula (III) compound and the reaction of orthoformate and formula (IV) compound ^；
Figure IMGF000004_0001
Iii) by formula (V) compound, cyclization obtains formula (VI) compound in the basic conditions:
Figure IMGF000004_0002
Iv) formula (VI) compound hydrolysis is obtained into formula (I) compound it is a further object of the present invention to provide some formulas (Π) compound:
R,
Figure IMGF000004_0003
(Π) Wherein following compounds are novel compounds,
Rj is H, C1;
R2For C1;
R3For F,（^-(4Alkoxy, CN;
R7For Cl.The present invention is described in detail
In the method that the present invention prepares formula (I) compound, in formula (I) compound is preferably hydrogen, fluorine or amino, preferably fluorine or chlorine； R3Preferably fluorine, CN or OCH3 ;Preferably cyclopropyl, cyclohexyl.
(II) reaction of formula compound and carbonic ester can be carried out with methyl carbonate or ethyl ester, and the reaction generally in organic solvent, is carried out in the presence of alkali.It is preferred that with carbonic ester in itself as solvent, sodium hydride or sodium alkoxide may be selected in alkali used.The reaction of formula (III) compound and orthoformate is generally carried out in the presence of acetic anhydride, after reaction directly with formula (IV) R4NH2Reaction obtains formula (V) compound.The cyclisation of formula (V) reactant is carried out in organic solvent in the basic conditions, and solvent preferably uses DMF, and alkali then can select Anhydrous potassium carbonate, so as to obtain formula (VI) compound.After cyclization, corresponding quinolone carboxylic acid ester is obtained with this area conventional method and is hydrolyzed to the corresponding compound carboxylic acid of formula 00.In the method for prepare compound formula (I) of the present invention, work as R1For NH2When, it can be converted from 1^ for the corresponding formula of halogen (VI) compound, reaction is such as shown：
Figure IMGF000006_0001
In formula (Π) prepared by the present invention ' it is preferably H, R3Preferably F, OCH3, CN.Formula (Π) compound be prepared by a variety of methods carry out ' carried out from the phenyl polyhalide being easy to get in the present invention.With specific embodiment, the invention will be further described below.The preparation of quinolione acid
Embodiment 1 prepares Moses's carboxylic acid from the chloro- 5- oxygen -3- methoxyacetophenones of 2,4- bis- Prepare the fluoro- 3- methoxybenzoyls acetic acid methyl esters of the chloro- 5- of 2,4- bis-
By 2,4- dichloro-5-fluoro-3-methoxy acetophenones 80.6g (0.34mol), dimethyl carbonate 1000ml stirring mixing.Content is added portionwise at room temperature for 50% NaH 50.0g (1.04mol), finishes and reacts 3h in 80 °C.Reactant is carefully poured into the frozen water containing a small amount of acetic acid, extracted with ether, is washed, anhydrous sodium sulfate drying.Ether is steamed, is reclaimed after excessive dimethyl carbonate, residue is recrystallized in methyl alcohol, obtains the fluoro- 3- methoxybenzoyls bases of the chloro- 5- of 2,4- bis--methyl acetate 80.8g (0.274mol), mp 50-53 °C, yield 80.6%.Prepare the sour methyl esters of 2- (the fluoro- 3- methoxybenzoyls bases of the chloro- 5- of 2,4- bis-) -3- cyclopropylamino acrylates
By the fluoro- 3- methoxybenzoyls acetic acid methyl ester 73.8g (0.25mol) of the chloro- 5- of 2,4- bis-,
66.6g triethyl orthoformates (0.45mol) and 77.4g acetic anhydrides (0.72mol) stirring mixing, 2.5h are reacted at 150 °C, decompression steams low boiling fraction.250ml absolute methanols are added into residue; cyclopropylamine 14.5g (0.25mol) is added under frozen water cooling; finish and react 2h at room temperature; suction filtration; recrystallized with petroleum ether-hexamethylene double solvents; obtain 2- (2, the 4- bis- chloro- fluoro- 3- methoxybenzoyls bases of 5-) -3- cyclopropylamino acrylates acid methyl esters 66.0g (0.182mol), yield 72.9%.Prepare the fluoro- 8- methoxyl groups -1,4- dihydros -4- Oxoquinoline-3-carboxylic acid methyl esters of the chloro- 6- of 1- cyclopropyl -7-
2- (2, the 4- bis- chloro- fluoro- 3- methoxybenzoyls bases of 5-) -3- cyclopropylamino acrylates acid methyl esters 62.6g (0.173mol) is dissolved in 220ml DMF, anhydrous K is added2CO334.7g (0.35mol), in 40-45 stirring reactions 2.5h, TLC tracking.Reactant is poured into 800ml frozen water, solid is filtered out, is fully washed with water 100ml X 2, drying, flowed back 15 minutes with 95% methanol 120ml again, cooling, is filtered, and is dried, obtain the fluoro- 8- methoxyl groups -1 of the chloro- 6- of white solid 1- cyclopropyl -7-, 4- dihydro -4- Oxoquinoline-3-carboxylic acid methyl esters 50.8g (0.156mol), mp 184-187 °C, yield 90.1%.Prepare the fluoro- 8- methoxyl groups -1,4- dihydros -4- Oxoquinoline-3-carboxylic acids of the chloro- 6- of 1- cyclopropyl -7-
By the fluoro- 8- methoxyl groups -1 of the chloro- 6- of 1- cyclopropyl -7-, 4- dihydro -4- Oxoquinoline-3-carboxylic acid methyl esters 28.6g (0.088mol), acetic acid 160ml, water 100ml and the concentrated sulfuric acid 18ml mixture were in 100-110 °C of stirring reaction 40 minutes.Reaction mass is cooled down, filtering.Precipitation is recrystallized with chloroform-ethanol, obtains the fluoro- 8- methoxyl groups-Isosorbide-5-Nitrae-dihydro -4- Oxoquinolines -3- of the chloro- 6- of product 1- cyclopropyl -7- Carboxylic acid (Moses's carboxylic acid) 25.2g (0.081mol), mp 195-199 °C, yield 91.8%.Embodiment 2 prepares 8- quinolone carbonitriles carboxylic acid from the chloro- 5- fluoro acetophenones of 3- cyano group -2,4- bis- and prepares the chloro- 5- fluorobenzoyls ethyl of 3- cyano group -2,4- bis-
By the chloro- 5- fluoro acetophenones 78.9g (0.34mol) of 3- cyano group -2,4- bis-, diethyl carbonate
1000ml stirring mixing, is added portionwise content for 50% NaH 50.0g (1.04mol), finishes in 80 at room temperature.C reacts 3h.Reactant is carefully poured into the frozen water containing a small amount of acetic acid, extracted with ether, is washed, anhydrous sodium sulfate drying.Ether is steamed, is reclaimed after excessive diethyl carbonate, residue is recrystallized in toluene, obtains the chloro- 5- fluorobenzoyls ethyl 86.6g (0.285mol) of 3- cyano group -2,4- bis-, yield 83.7%.Prepare 2- (the chloro- 5- fluoro benzoyls of 3- cyano group -2,4- bis-) -3- cyclopropylamino acrylate acetoacetic esters
By 3- cyano group -2; the chloro- 5- fluorobenzoyls ethyl 76.0g (0.25mol) of 4- bis-; 66.6g triethyl orthoformates (0.45mol) and 77.4g acetic anhydrides (0.72mol) stirring mixing; 2.5h is reacted at 150 °C, decompression steams low boiling fraction.250ml absolute ethyl alcohols are added into residue, cyclopropylamine 14.5g (0.25mol) is added under frozen water cooling.Finish and react 2h at room temperature; suction filtration; recrystallized with petroleum ether-hexamethylene double solvents; obtain 2- (3- cyano group -2; the chloro- 5- fluoro benzoyls of 4- bis-) -3- cyclopropylamino acrylate acetoacetic ester 65.0g (0.175mol); mp 125-129 °C, yield 70.1%.Prepare the fluoro- Isosorbide-5-Nitraes of the 8- chloro- 6- of cyano group -1- cyclopropyl -7--dihydro -4- Oxoquinoline-3-carboxylic acid ethyl esters
2- (the chloro- 5- fluoro benzoyls of 3- cyano group -2,4- bis-) -3- cyclopropylamino acrylate acetoacetic ester 64.2g (0.173mol) are dissolved in 220ml DMF, anhydrous K is added2C0334.7g (0.35mol), in 40-45 stirring reactions 2.5h, TLC tracking.Reactant is poured into 800ml frozen water, solid is filtered out, is fully washed with water 100ml X 2, drying, flowed back 15 minutes with 95% ethanol 120ml again, cooling, is filtered, and is dried, obtain the chloro- 6- of white solid S- cyano group -1- cyclopropyl -7- fluoro- 1,4- dihydro -4- Oxoquinoline-3-carboxylic acid ethyl ester 53.2g (0.159mol), mp 196-199 °C, yield 91.9%.Prepare the fluoro- 1,4- dihydros -4- Oxoquinoline-3-carboxylic acids of the chloro- 6- of 8- cyano group -1- cyclopropyl -7- By the chloro- 6- of 8- cyano group -1- cyclopropyl -7- fluoro- 1,4- dihydro -4- Oxoquinoline-3-carboxylic acid ethyl ester 29.4g (0.088mol), acetic acid 160ml, water 100ml and the concentrated sulfuric acid 18ml mixture were in 100-110 °C of stirring reaction 40 minutes.Reaction mass is cooled down, and filtering, precipitation is recrystallized with chloroform-ethanol, obtain the chloro- 6- of product 8- cyano group -1- cyclopropyl -7- fluoro- 1,4- dihydro -4- Oxoquinoline-3-carboxylic acids 23.8g (0.0775mol), mp 288-293 °C, yield 88.1%.Embodiment 3 is from phenyl-pentafluoride ethyl ketone preparation department carboxylic acid fluoride
Prepare pentafluorobenzoyl ethyl acetate
By phenyl-pentafluoride ethyl ketone 71.4g (0.34mol), diethyl carbonate 1000ml stirring mixing is added portionwise content for 50% NaH 50.0g (1.04mol), finished in 80 °C of reactions at room temperature
3h.Reactant is carefully poured into the frozen water containing a small amount of acetic acid, extracted with ether, is washed, anhydrous sodium sulfate drying.Ether is steamed, is reclaimed after excessive diethyl carbonate, decompression steams pentafluorobenzoyl ethyl acetate（112-121.C/8 Pa) fraction 80.5g (0.286mol), yield 84.0%.Prepare 2- (pentafluorobenzoyl) -3- cyclopropylamino acrylate acetoacetic esters
By pentafluorobenzoyl ethyl acetate 70.5g (0.25mol); 66.6g triethyl orthoformates (0.45mol) and 77.4g acetic anhydrides (0.72mol) stirring mixing; 2.5h is reacted at 150 °C, decompression steams low boiling fraction.250ml absolute ethyl alcohols are added into residue and add cyclopropylamine 14.25g (0.25mol) under frozen water cooling.Finish and react 2h at room temperature, suction filtration is recrystallized with petroleum ether-hexamethylene, obtains 2- (pentafluorobenzoyl) -3- cyclopropylamino acrylate acetoacetic ester 62.8g (O.lSmol), mp 88-91 °C, yield 720%.Prepare 1- cyclopropyl -5,6,7,8- tetra- fluoro- Isosorbide-5-Nitraes-dihydro -4- Oxoquinoline-3-carboxylic acid ethyl esters
By 2- (pentafluorobenzoyl) -3- cyclopropylamino acrylates acetoacetic ester 60.4g(0.173mol), is dissolved in 220ml DMF, adds anhydrous K2CO334.7g (0.35mol), in 40-45 °C of stirring reaction 2.5h, TLC tracking.Reactant is poured into 800ml frozen water, solid is filtered out, is fully washed with water 100ml X 2, thousand are dried, then is flowed back 15 minutes with 95% ethanol 120ml, cooling, filtering, dries, obtains white solid 1- cyclopropyl -5,6,7,8- tetra- fluoro- Isosorbide-5-Nitraes-dihydro -4- Oxoquinoline -3- carboxylic acid, ethyl esters 53.0g (0.161mol), mp 169-171 °C, yield 93%. Prepare 5- benzamido group -1- cyclopropyl -6,7,8- tri- fluoro- Isosorbide-5-Nitraes-dihydro -4- Oxoquinoline-3-carboxylic acids ethyl ester is by 1- cyclopropyl -5,6,7,8- tetra- fluoro- Isosorbide-5-Nitraes-dihydro -4- Oxoquinoline-3-carboxylic acid ethyl ester 53.0g (0.161mol), benzylamine 15.4ml, Anhydrous potassium carbonate 37.0g and acetonitrile 220ml mixture steam solvent in 100-110 °C of agitating and heating lh, TLC tracking.Residue is recrystallized in ethanol.Obtain 5- benzamido group -1- cyclopropyl -6,7, the fluoro- Isosorbide-5-Nitraes of 8- tri--dihydro -4- Oxoquinolines _ 3- carboxylic acid, ethyl esters 53.7g (0.129mol), mp 133-135 °C, yield 80.0%.Prepare 5- amino -1- cyclopropyl -6,7, the fluoro- Isosorbide-5-Nitraes of 8- tri--dihydro -4- Oxoquinoline-3-carboxylic acid ethyl esters
By 5- benzamido group -1- cyclopropyl -6,7,8- tri- fluoro- 1,4- dihydro -4- Oxoquinoline-3-carboxylic acid ethyl esters 46.2g (O.l l lmol), the in the mixed solvent of 200ml acetic acid and ethanol is dissolved in, the Pd/C catalyst of 0.5g 5% is added, H is passed through at room temperature2, TLC tracking, reaction about 3h.Solid product is filtered out, and is dissolved in chloroform, is refiltered, catalyst is removed.Filtrate steams solvent, and residue is recrystallized in chloroform-ethanol double solvents, obtains 5- amino -1- cyclopropyl -6,7,8- tri- fluoro- Isosorbide-5-Nitraes-dihydro -4- Oxoquinoline-3-carboxylic acid ethyl ester 32.4g (0.0944mol), mp 235-237, yield 85.0%.Prepare 5- amino -1- cyclopropyl -6,7, the fluoro- Isosorbide-5-Nitraes of 8- tri--dihydro -4- Oxoquinoline-3-carboxylic acids
By 5- amino -1- cyclopropyl -6,7,8- tri- fluoro- Isosorbide-5-Nitraes-dihydro -4- Oxoquinoline-3-carboxylic acid ethyl ester 28.7g (0.088mol), acetic acid 160ml, water 100ml and the concentrated sulfuric acid 18ml mixture are in 10 °C of 100-1 stirring reactions 40 minutes.Reaction mass is cooled down, filtering.Precipitation is recrystallized with chloroform-ethanol, obtains product 5- amino -1- cyclopropyl -6,7,8- tri- fluoro- 1,4- dihydro -4- Oxoquinoline-3-carboxylic acids (department's carboxylic acid fluoride) 25.6g (0.086mol), mp 293-295 °C, yield 98.0%.Chloro- 3, the 5- difluoro acetophenones preparation department carboxylic acid fluoride of embodiment 4 from 2,4,6- tri-
Prepare chloro- 3, the 5- difluorobenzoyls ethyls of 2,4,6- tri-
By 2,4,6- tri- chloro- 3,5- difluoro acetophenones 88.2g (0.34mol), diethyl carbonate l, 000ml stirring mixing, content is added portionwise at room temperature for 50% NaH 50.0g (1.04mol), finishes and reacts 3h in 80.Reactant is carefully poured into the frozen water containing a small amount of acetic acid, extracted with ether, is washed, anhydrous sodium sulfate drying.Ether is steamed, is reclaimed after excessive diethyl carbonate, residue is recrystallized in toluene, obtains 2,4,6- tri- chloro- 3,5- difluorobenzoyls ethyls 93.3g (0.276mol), yield 81 2%.Prepare 2- (2,4,6- tri- chloro- 3,5- difluoro benzoyls) -3- cyclopropylamino acrylate acetoacetic esters
By 2; 4; 6- tri- chloro- 3; 5- difluorobenzoyl ethyl 82.9g (0.25mol); 66.6g triethyl orthoformates (0.45mol) and 77.4g acetic anhydrides (0.72mol) stirring mixing; 2.5h is reacted at 150 °C, decompression steams low boiling fraction.250ml absolute ethyl alcohols are added into residue, cyclopropylamine 14.5g (0.25mol) is added under frozen water cooling.Finish and react 2h at room temperature, suction filtration is recrystallized with petroleum ether-hexamethylene double solvents; obtain 2- (2,4,6- tri- chloro- 3; 5- difluoro benzoyls) -3- cyclopropylamino acrylate acetoacetic ester 74.5g (0.187mol), yield 74.6%.Prepare the chloro- 6,8 2 fluoro- 1,4- dihydros -4- Oxoquinoline-3-carboxylic acid ethyl esters of 1- cyclopropyl -5,7- two
By 2- (the chloro- 3,5- difluoro benzoyls of 2,4,6- tri-) -3- cyclopropylamino acrylate acetoacetic esters 68..9g(0.173mol), is dissolved in 220ml DMF, adds anhydrous K2CO334.7g (0.35mol), in 40-45 °C of stirring reaction 2.5h, TLC tracking.Reactant is poured into 800ml frozen water, solid is filtered out, is fully washed with water 100ml X 2, drying, then is flowed back 15 minutes with 95% ethanol 120ml, is cooled down, filtering.Dry, obtain white solid 1- cyclopropyl -5,7- bis- chloro- 6,8 two fluoro- Isosorbide-5-Nitraes-dihydro -4- Oxoquinoline-3-carboxylic acid ethyl ester 60.4g (0.167mol), mp 191-195 °C, yield 96.4%.Prepare the fluoro- 1,4- dihydros -4- Oxoquinoline-3-carboxylic acid ethyl esters of 5- benzyl amino -1- cyclopropyl -7- chloro- 6,8 2
By 1- cyclopropyl -5,7- bis- chloro- 6,8 two fluoro- 1,4- dihydro -4- Oxoquinoline-3-carboxylic acid ethyl ester 58.3g (0.161mol), benzylamine 15.4ml, Anhydrous potassium carbonate 37.0g and acetonitrile 220ml mixture steam solvent in 100-110 °C of agitating and heating lh, TLC tracking.Residue is recrystallized in ethanol, obtains the fluoro- Isosorbide-5-Nitraes of 5- benzyl amino -1- cyclopropyl -7- chloro- 6,8 two-dihydro -4- Oxoquinoline -3- carboxylic acid, ethyl esters 58.3g (0.135mol), yield 83.7%.Prepare 5- amino -1- cyclopropyl -7- chloro- 6,8 two fluoro- 1,4- dihydros -4- Oxoquinoline-3-carboxylic acids ethyl ester is by 5- benzyl amino -1- cyclopropyl -7- chloro- 6,8 two fluoro- 1,4- dihydro -4- Oxoquinoline-3-carboxylic acid ethyl esters 48.0g (0.11 lmol), the in the mixed solvent of 220ml acetic acid and ethanol is dissolved in, 0.5g is added 5% Pd/C catalyst, is passed through H at room temperature2, TLC tracking, reaction about 3h.Solid product is filtered out, and is dissolved in chloroform, is refiltered, catalyst is removed.Filtrate steams solvent, and residue is recrystallized in chloroform-ethanol double solvents, obtains the fluoro- Isosorbide-5-Nitraes of 5- amino -1- cyclopropyl -7- chloro- 6,8 two-dihydro -4- Oxoquinoline-3-carboxylic acid ethyl ester 32.0g (0.093mol), yield 83.9%.Prepare the fluoro- 1,4- dihydros -4- Oxoquinoline-3-carboxylic acids of 5- amino -1- cyclopropyl -7- chloro- 6,8 2
By 5- amino -1- cyclopropyl -7- chloro- 6,8 two fluoro- 1,4- dihydro -4- Oxoquinoline-3-carboxylic acid ethyl ester 30.1g (0.088mol), acetic acid 160ml, water 100ml and the concentrated sulfuric acid 18ml mixture were in 100-110 °C of stirring reaction 40 minutes.Reaction mass is cooled down, filtering.Precipitation is recrystallized with chloroform-ethanol, obtains the fluoro- Isosorbide-5-Nitraes of product 5- amino -1- cyclopropyl -7- chloro- 6,8 two-dihydro -4- Oxoquinolines
- 3- carboxylic acids (department's carboxylic acid fluoride) 26.8g (0.0852mol), mp 283-2S7 °C, yield 96.8%.The preparation of halo acetophenone
The preparation of the 2,4- dichloro-5-fluoro-3-methoxy acetophenones of embodiment 5
A. the chloro- 5- fluoronitrobenzenes of 2,4- bis- are prepared
By 60 milliliters of concentrated nitric acid（1.41 mole）, 93 milliliters of the concentrated sulfuric acid（1.75 mole）And 16.5 milliliters of water is made into nitration mixture.58.3 milliliters (0.50 mole of 2,4 dichloro fluorobenzene is added dropwise below 40）, reacted 2 hours at 50-60 °C.Material is poured into trash ice, filters, is washed to neutrality, dry pale yellow crystals 2,99.9 grams (0.476 mole of the chloro- 5- fluoronitrobenzenes of 4- bis-）, yield 95.1%. mp 39-42 °C.
B. the chloro- 5- fluoronitrobenzenes of the bromo- 2,4- bis- of 3- are prepared
The chloro- 5- fluoronitrobenzenes of 2,4- bis- 96.6 grams (0.46 moles) and 1150 milliliters of glacial acetic acid containing 9.7 milliliters of bromines are stirred into mixing, then are slowly added into the solution that 690 milliliters of concentrated sulfuric acids and 464 milliliters of water are made into.67.5 grams of potassium bromates are added in reaction solution in seven times under 40（9.65 grams every time）, add within about 2 hours.Stop reaction after 8 hours.Slowly material is poured into 3,000 dissolved with 46.0 grams of sodium hydrogensulfites milliliter of aqueous solution, stood overnight.Filtering, uses warm water（30 °C or so）Washing 3-4 times, drying, obtains chloro- 122.1 grams of the 5- fluoronitrobenzenes of bromo- 2, the 4- bis- of faint yellow 3-（0.423 mole）, yield 91.9%. mp 51-53.5°C.
C. the fluoro- 3- methoxy nitrobenzenes of the chloro- 5- of 2,4- bis- are prepared
By fluorine-based 120 grams of the nitre benzene of the chloro- 5- of the bromo- 2,4- bis- of 3-（0.415 mole）, the milli of methanol 500 Rise, (0.498 mole) stirring mixing of 26.9 grams of sodium hydroxide 1.66g (0.042 mole) and sodium methoxide is reacted 4 hours at 60 °C.With ether extractive reaction product, water, watery hydrochloric acid and water washing are being used successively, anhydrous sodium sulfate drying is used.Solvent is steamed, residue is recrystallized in ethanol, obtain fluoro- 73.5 grams of the 3- methoxy nitrobenzenes (0.306 mole) of the chloro- 5- of 2,4- bis-, yield 73.8%.
D. the fluoro- 3- aminoanisoles of the chloro- 5- of 2,4- bis- are prepared
By fluoro- 72.0 grams of the 3- methoxy nitrobenzenes (0.3 mole) of the chloro- 5- of 2,4- bis-, 500 ml methanols and 2.65 grams of palladium-Pd/carbon catalysts, in the case where hydrogen pressure is 3MPa, 60 °C are reacted 3 hours.Reaction mass is as cold as room temperature, filters out catalyst, steams solvent, obtains fluoro- 58.5 grams of the 3- aminoanisoles of the chloro- 5- of 2,4- bis-（0.279 mole）, yield 92.9%.
E. the fluoro- 3- methoxybromobenzenes of the chloro- 5- of 2,4- bis- are prepared
By fluoro- 52.5 grams of the 3- aminoanisoles of the chloro- 5- of 2,4- bis-（0.25 mole）, be added to 70 165 milliliters of hydrochloric acid-water（1 :1) in solution, pasty state is stirred into, 0-5 °C is as cold as.18.2 grams of natrium nitrosum was added dropwise in 30 minutes（0.263 mole）The solution being made into 50 milliliters of water.The diazo solution of gained is slowly added in the solution that cuprous bromide (0.299 mole) and 160 milliliters of hydrobromic acids (HBr) are made into, stirs 2 hours, stand overnight.Steam distillation, distillate is extracted with toluene.Oil reservoir uses 10% sodium hydrate aqueous solution, the concentrated sulfuric acid and water washing, anhydrous sodium sulfate drying successively.Solvent is steamed, residue silica gel makees stationary phase, just own protective embankment-dichloromethane makees mobile phase, carry out column chromatography, obtain fluoro- 58.1 grams of the 3- methoxybromobenzenes of the chloro- 5- of 2,4- bis-（0.212 mole）, yield 84.9%.
F. 2,4- dichloro-5-fluoro-3-methoxy acetophenones are prepared
By fluoro- 0.20 mole of the 3- methoxybromobenzenes of the chloro- 5- of 2,4- bis-, 0.22 mole of magnesium powder, initiation is stirred at room temperature in 240 milliliters of 0.24 mole of stannous chloride and tetrahydrofuran, and then quick cooling, makes reaction be carried out under -30 ± 10 °C.TLC tracking reactions are complete.The chloroacetic chloride being dissolved in 50 milliliters of toluene is added dropwise again（0.3 mole）, reacted 8 hours at -30 ± 10 °C.Reaction is raised to room temperature, stir 3 hours.Material is poured into 170 grams of trash ices containing 75 milliliter 25% of sulfuric acid, stirred 5 minutes.Organic phase is separated, water layer is extracted with toluene.Merge organic layer, successively with sodium-chloride water solution, the aqueous solution and water washing of sodium acid carbonate, anhydrous sodium sulfate drying.Decompression steams solvent, and residue is recrystallized in ethanol, obtains 38.7 grams of 2,4- dichloro-5-fluoro-3-methoxy acetophenones（0.163 mole）, yield 81.6%. mp 36:7-39.4°C. The preparation of the 3- cyano-2,4-dichloro-5-fluoro acetophenones of embodiment 6
A. the chloro- 5- fluoronitrobenzenes of 3- cyano group -2,4- bis- are prepared
By chloro- 120 grams of (0.415 gram molecules of 5- fluoronitrobenzenes of the bromo- 2,4- bis- of 3- prepared by the method for embodiment 5）, anhydrous 36.9 grams of cuprous cyanide (0.46 gram molecule) and 200 milliliters of DMF are stirred and heated to 100 °C, reacted 6 hours in anhydrous conditions.TLC tracking reactions are complete.Material is as cold as room temperature, (5.5 milliliters of ferric trichloride (83 grams) and concentrated hydrochloric acid is poured into）And the aqueous solution that 830 milliliters of water is made into, stirred 30 minutes at 50-60 °C.Extracted again with ether, organic layer brine It, anhydrous magnesium sulfate is dried.Solvent is steamed, it is that mobile phase carries out column chromatography that residue, which makees stationary phase, toluene with silica gel,.Obtained crude product again with methanol recrystallization, obtains 58.5 grams of the chloro- 5- fluoronitrobenzenes of 3- cyano group -2,4- bis- (0.249 gram molecule), fusing point, yield 60.0%.
B. the chloro- 5- fluoroanilines of 3- cyano group -2,4- bis- are prepared
By 27.0 grams of (0.247 gram molecules of chloro- 5- fluoronitrobenzenes of 3- cyano group -2,4- two）, 500 milliliters of ethanol and 2.18 grams of palladium-Pd/carbon catalysts, under hydrogen pressure 3MPa, 60 reactions 3 hours.Reaction mass is as cold as room temperature, filters out catalyst, steams solvent, obtains 48.0 grams of (0.234 gram molecules of chloro- 5- fluoroanilines of 3- cyano group -2,4- bis-）, yield 94.7%.
C prepares the chloro- 5- bromofluorobenzenes of 3- cyano group -2,4- two
By 47.2 grams of (0.23 gram molecules of chloro- 5- fluoroanilines of 3- cyano group -2,4- two）, it is added to 70 °C of the water (1 of 150 milliliters of hydrochloric acid one:1) in solution, pasty state is stirred into.0-5 C are as cold as, the solution that 16.7 grams of natrium nitrosum (0.242 gram molecule) and 46 milliliters of water are made into was added dropwise in 30 minutes.The diazo solution of gained is slowly added in the solution that cuprous bromide (0.275 gram molecule) and 147 milliliters of hydrobromic acids (HBr) are made into, stirs 2 hours, stand overnight.Steam distillation, with toluene extraction it is leavened go out liquid, oil reservoir uses 10% sodium hydrate aqueous solution, the concentrated sulfuric acid and water washing, anhydrous sodium sulfate drying successively.Solvent is steamed, residue is recrystallized in toluene, obtain 53.3 grams of (0.198 gram molecules of chloro- 5- bromofluorobenzenes of 3- cyano group -2,4- bis-）, yield 86.2%.
D. the chloro- 5- fluoro acetophenones of 3- cyano group -2,4 two are prepared
By 3- cyano group -2,216 milliliters of the chloro- gram molecules of 5- bromofluorobenzenes 0.18 of 4- bis-, the gram molecule of magnesium powder 0.198, the gram molecule of stannous chloride 0.216 and tetrahydrofuran are stirred at room temperature after initiation, quick cooling immediately, makes reaction (be carried out -30 ± 1 under TC.TLC tracking reactions are complete.21.2 grams of the chloroacetic chloride (0.27 gram molecule) being dissolved in 45 milliliters of toluene is added dropwise again, is reacted 8 hours under -30 ± 10 °C.Reaction temperature is raised to room temperature, stir 3 hours, material is poured into containing 75 milliliters In 150 grams of trash ices of dilute sulfuric acid (25% concentration), stir 5 minutes.Organic layer is separated, water layer is extracted with toluene.Merge organic layer, successively with sodium-chloride water solution, sodium bicarbonate aqueous solution and water washing, anhydrous sodium sulfate drying.Decompression steams solvent, and residue is recrystallized in ethanol, obtains the chloro- gram molecule of 5- fluoro acetophenones 0.148 of 3- cyano group -2,4- bis-, yield 82.3%. mp 94.3-96.0 °C.Chloro- 3, the 5- difluoro acetophenones of embodiment 72,4,6- tri-
A. chloro- 2, the 4- difluoro nitrobenzenes of 3,5- bis- are prepared
100ml carbon tetrachloride and 2,4- difluoro nitrobenzene 30.2g (0.19mol) are added to reflux condenser, in the there-necked flask of thermometer and agitator, Cl is passed through at a reflux temperature2About 3 hours, TLC tracking.After reaction terminates, carbon tetrachloride is steamed, residue is recrystallized in ethyl acetate, obtain chloro- 2, the 4- difluoro nitrobenzenes 39.0g (0.171mol) of 3,5- bis-, yield 90.0%, m.p. 41-44 ° (：.
B. chloro- 2, the 4- difluoroanilines of 3,5- bis- are prepared
Chloro- 2, the 4- difluoro-nitrobenzenes 38.5g (0.169mol) of 3,5- bis- and 1.49g palladium-Pd/carbon catalyst are added in 100ml autoclaves, in the case where pressure is 3Mpa, is reacted 3 hours at 60 °C.Reaction mass is as cold as room temperature, filters out catalyst, distillation, obtains chloro- 2, the 4- difluoroanilines 31.8g (0.161mol) of 3,5- bis-, yield 95.1%.
C. 2,4- bis- fluoro- 1,3,5- trichloro-benzenes are prepared
Chloro- 2, the 4- difluoroanilines 31.1g (0.157mol) of 3,5- bis- are added in 70 °C of 100ml hydrochloric acid-water（1 :1) pasty state, is stirred into.0-5 is as cold as, the solution that natrium nitrosum 11.6g (0.165mol) and water are made into was added dropwise in 30 minutes.Gained diazonium salt solution is slowly added in the solution that CuCl (0.188mol) and hydrochloric acid 100ml are made into, stirs 2 hours, stands overnight.Steam distillation, extracts distillate, successively with the 10% NaOH aqueous solution, dense H with toluene2S04With 0 washing, anhydrous Na2SO4Dry.Solvent is steamed, residue is recrystallized in toluene, obtain 2,4- bis- fluoro- 1,3,5- trichloro-benzenes 27.7g (0.127mol), yield 81.1%.
D. 2,4,6- tri- chloro- 3,5- difluoro bromobenzenes are prepared
By 2,4- bis- fluoro- 1, the glacial acetic acid that 3,5- trichloro-benzenes 27g (0.124mol) and 310ml contain 2.6ml bromines is added in reaction bulb, is slowly added into 186ml dense 11 again under agitation2804The solution being made into 125ml water.Again by 18.2g KBrO under being stirred at 45 °C3(each 2.6g) adds in seven times Enter in reaction bulb, about 1 hour plus 1 time.Stop reaction after 8 hours.Material is poured into dissolved with NaHSO3In the 1 of 12.4g, 000 milliliter of aqueous solution, stand overnight, filter, washed 3-4 times with warm water (30 or so), dry, obtain 2,4,6- tri- chloro- 3,5- difluoro bromobenzenes 34.1g (0.115mol), yield 92.9%.
E. chloro- 3,5 difluoro acetophenones of 2,4,6- tri- are prepared
By 3,5- bis- fluoro- 2,4,6 three chloro-bromobenzene O.lmol, magnesium powder O.l lg-atom, stannous chloride 0.12mol and THF 120ml are stirred at room temperature, until reactant blackening, show that reaction has triggered.Quick cooling, makes reaction be carried out under -30 °C ± 10 °C immediately.Tracked with GLC.When the chloroacetic chloride 11.78g (0.15mol) being dissolved in 25ml toluene is added dropwise after bromo- 3, the 5- bis- fluoro- 2 of 1-, 4,6- trichloro-benzenes reaction completely, reacted 8 hours under -30 ± 10 °C.Reaction temperature is raised to room temperature again, stir 3 hours.Reaction mass is poured into the trash ice that 150g contains 75ml dilute sulfuric acids (25%), stirred 5 minutes.Organic layer is separated, water layer is extracted with toluene 30mlx2.Merge organic layer, successively with saturation NaCl aqueous solution 45ml, saturation NaHC03Aqueous solution 45ml, water 45ml and saturation NaCl aqueous solution 25ml washings.Decompression steams toluene, and residue is recrystallized in toluene, obtains 3,5- bis- fluoro- 2,4,6- trichloroacetophenone 0.0819mol, yield 81.9%. mp 73-76.C.

Claims (1)

  1. Claim
    1. a kind of preparation method of formula (I) quinolonecarboxylic acid,
    Figure IMGF000017_0001
    Wherein：For 11, halogen atom, amino,
    R2For halogen atom,
    R3For hydrogen, halogen atom, ^- (4Protective embankment epoxide, CN,
    R4For C3-C6Ring institute base, C C4 Ci- C4Complete epoxide C!- C^ burns base, c1-c4i^ ,S c c4^¾,
    Including step：
    I) by formula (Π) compound
    Wherein R, R2,R3It is defined as above, R7For halogen atom,
    Formula (Ι Π) compound is obtained with carbonate reaction,
    10
    Figure IMGF000018_0001
    Wherein, R8Represent methyl or ethyl；
    ) with formula (III) compound successively with orthoformate and formula (IV) compound R4NH2Reaction obtains formula (V) compound；
    Figure IMGF000018_0002
    Iii) by formula (V) compound, cyclization obtains formula (VI) compound in the basic conditions;
    Figure IMGF000018_0003
    ) formula (VI) compound hydrolysis is obtained into formula (I) compound.
    2. method according to claim 1, wherein, R, selected from H, fluorine, chlorine, amino； R2Selected from chlorine, fluorine； 13Selected from fluorine, chlorine, CN, Cr0 alkoxy； R4Selected from C3- C6Cycloalkyl.
    3. method according to claim 2, wherein
    R3Selected from fluorine, CN, OCH3;
    R4Selected from C3- ( 6Cycloalkyl.
    4. method according to claim 3, wherein
    1^ is selected from hydrogen, fluorine, amino；
    R2Selected from fluorine；
    R4Selected from cyclopropyl, cyclohexyl.
    5. method according to claim 1, wherein further including
    In step iv) by the compound for halogen atom be converted into it is corresponding be amino-compound the step of.
    Formula 6. (II) compound
    Figure IMGF000019_0001
    Wherein ^ is C1;For（：1； R3For F, C ,-C4Alkoxy, CN; R7For
    7. compound according to claim 6, wherein 13For OCH^I:l CN.
    8. compound according to claim 7, wherein 1^ are 11.
    9. compound according to claim 6, wherein 1^ are 11, it is.
CN01814188.9A 2000-08-16 2001-07-06 New process for preparing quinolone-carboxylic acid Expired - Fee Related CN1219769C (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
CN00123446.3 2000-08-16
CN00123446.3A CN1338455A (en) 2000-08-16 2000-08-16 Process for preparing quinolone carboxylic acid
PCT/CN2001/001156 WO2002059094A1 (en) 2000-08-16 2001-07-06 A new process for preparing a quinolone-carboxylic acid

Publications (2)

Publication Number Publication Date
CN1447797A true CN1447797A (en) 2003-10-08
CN1219769C CN1219769C (en) 2005-09-21

Family

ID=4589879

Family Applications (2)

Application Number Title Priority Date Filing Date
CN00123446.3A Pending CN1338455A (en) 2000-08-16 2000-08-16 Process for preparing quinolone carboxylic acid
CN01814188.9A Expired - Fee Related CN1219769C (en) 2000-08-16 2001-07-06 New process for preparing quinolone-carboxylic acid

Family Applications Before (1)

Application Number Title Priority Date Filing Date
CN00123446.3A Pending CN1338455A (en) 2000-08-16 2000-08-16 Process for preparing quinolone carboxylic acid

Country Status (7)

Country Link
US (1) US6699992B2 (en)
EP (1) EP1319656B1 (en)
JP (1) JP2004517149A (en)
CN (2) CN1338455A (en)
AT (1) ATE337304T1 (en)
DE (1) DE60122539T2 (en)
WO (1) WO2002059094A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111989314A (en) * 2018-04-25 2020-11-24 拜耳动物保健有限责任公司 Process for hydrolysis of quinolone formates

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100519158B1 (en) * 2002-12-21 2005-10-06 주식회사유한양행 A process for preparation of quinolone carboxylate derivatives
US8187483B2 (en) * 2006-08-11 2012-05-29 Jason Plumhoff Method to minimize CD etch bias
WO2008115890A2 (en) * 2007-03-19 2008-09-25 Takeda Pharmaceutical Company Limited Mapk/erk kinase inhibitors
US20090043646A1 (en) * 2007-08-06 2009-02-12 International Business Machines Corporation System and Method for the Automated Capture and Clustering of User Activities
CN102260172B (en) * 2011-03-30 2013-11-06 山东先达农化股份有限公司 Method for preparing 2-chloro-5-alkylcarbonyl acetyl-4-fluorophenoxyacetyl compound
CN103450068B (en) * 2012-05-27 2015-09-16 重庆常捷医药化工有限公司 A kind of synthetic method of Ziprasidone intermediate
CN107987074B (en) * 2017-10-27 2020-12-29 浙江美诺华药物化学有限公司 Synthetic method of prafloxacin
CN114933543B (en) * 2022-07-21 2022-10-28 山东国邦药业有限公司 Synthetic method of 3-cyclopropylamino-2- (2,4-dichloro-5-fluorobenzoyl) methyl acrylate

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4730000A (en) * 1984-04-09 1988-03-08 Abbott Laboratories Quinoline antibacterial compounds
US5075319A (en) * 1987-09-08 1991-12-24 Sterling Drug Inc. Pyridinyl-quinolone compounds, their preparation and use
NZ225926A (en) * 1987-09-08 1990-04-26 Sterling Drug Inc 7-pyridinyl-4-oxo-3-quinolinecarboxylic acid derivatives, and pharmaceutical compositions
ES2049640B1 (en) * 1992-06-18 1994-12-16 Genesis Para La Investigacion PROCEDURE FOR THE PREPARATION OF QUINOLIN CARBOXYLIC ACIDS.
DE69515882T2 (en) * 1994-08-02 2000-11-02 The Procter & Gamble Company, Cincinnati METHOD FOR PRODUCING ANTIMICROBIAL CONNECTIONS
JP2000119221A (en) * 1998-10-14 2000-04-25 Kyorin Pharmaceut Co Ltd Production of (2,4,5-trifluoro-3-methoxybenzoyl) acetic acid ester derivative and its production intermediate

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111989314A (en) * 2018-04-25 2020-11-24 拜耳动物保健有限责任公司 Process for hydrolysis of quinolone formates
CN111989314B (en) * 2018-04-25 2024-04-30 拜耳动物保健有限责任公司 Method for hydrolyzing quinolone formate

Also Published As

Publication number Publication date
EP1319656B1 (en) 2006-08-23
DE60122539D1 (en) 2006-10-05
EP1319656A4 (en) 2004-09-29
WO2002059094A1 (en) 2002-08-01
US20030166936A1 (en) 2003-09-04
JP2004517149A (en) 2004-06-10
ATE337304T1 (en) 2006-09-15
DE60122539T2 (en) 2007-05-03
CN1219769C (en) 2005-09-21
US6699992B2 (en) 2004-03-02
EP1319656A1 (en) 2003-06-18
CN1338455A (en) 2002-03-06

Similar Documents

Publication Publication Date Title
US7057067B2 (en) Process for the preparation of 2-halobenzoic acids
KR930004652B1 (en) Process for the quinolone carboxylic acid
CN1447797A (en) New process for preparing quinolone-carboxylic acid
KR19990028941A (en) Method for preparing N-substituted 3-hydroxypyrazole
JP2000212166A (en) Production of 1,3-dialkylpyrazole-4-carboxlic acid ester
EP1943209B1 (en) A process for preparing beta-ketoester compounds
WO1998047873A1 (en) Process for producing quinolone derivatives
EP0184035B1 (en) Quinolonecarboxylic acid derivatives and process for their preparation
CN113277984A (en) Method for preparing 3, 6-dichloropyridazin-4-ol
JP2002507586A (en) Intermediate preparation process
IE61737B1 (en) A process for preparing quinolone carboxylic acid intermediates
JP2556330B2 (en) Anisole derivative and method for producing the same
CN108329289B (en) Synthetic method of isocoumarin drug intermediate
JP2003506312A (en) Meta-nitrophenol derivative and method for producing the same
JP4148550B2 (en) 5-Amino-1-cyclopropyl-4-oxoquinoline-3-carboxylic acid derivative and process for producing the same
JP2013023476A (en) Method for producing 5-fluoro-1h-pyrazole-4-carboxylic acids
JP2716952B2 (en) Intermediate for producing 8-methoxyquinolone carboxylic acid derivative
JP2594017B2 (en) Intermediate for producing 8-methoxyquinolone carboxylic acid derivative
CN115124440A (en) Preparation method of prothioconazole intermediate
JP2853929B2 (en) Method for producing 2-chloro-4,5-difluoro-3-methoxybenzoic acid
CN111848552A (en) Preparation method and application of 3- (substituted phenyl) oxetane-3-carboxylic acid and intermediate thereof
KR950014221B1 (en) Preparation of intermediate of 8-methoxy quinolone carboxylic acid derivative
JP2021521238A (en) Hydrolysis process of quinolone carboxylic acid ester
JPH09100255A (en) Intermediate for producing 8-methoxyquinolonecarboxylic acid derivative
JPH01113396A (en) Production of (aryl)-(dimethyl)-(3-(4-fluoro-3- aryloxyphenyl) propyl)silane

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
C17 Cessation of patent right
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20050921

Termination date: 20110706